The present invention relates to microwave assisted chemical techniques. In particular, it relates to methods and apparatus for carrying out sophisticated chemical reactions, particularly organic synthesis and related types of reactions, with an emphasis on carrying out reactions rapidly in relatively small quantities to thereby more quickly evaluate larger numbers of reactants, products, by-products and chemical pathways.
The use of microwaves to provide the heat or the kinetic energy (or both) to drive certain types of chemical reactions is generally well understood. Microwaves are those waves within the portion of the electromagnetic spectrum with frequencies of between about 300 and 300,000 megahertz (MHz) and wavelengths of between about 1 centimeter and 1 meter. The borders between various types of electromagnetic radiation (e.g., visible, infrared, ultraviolet, etc.) are, however, arbitrary rather than definite. The terms are, however, well understood in their context and in this art.
Microwave radiation and microwave-assisted techniques are generally well-established for robust chemical reactions such as digestion and drying of suitable materials. More recently, the speed with which microwaves can apply energy to a reaction, and the fact that the microwave energy itself can drive the reaction rather than just creating heat to secondarily drive the reaction, has led to increased interest in using microwave radiation for more sophisticated chemical techniques, such as organic synthesis, particularly synthesis in relatively small quantities that are consistent with the needs of modern synthesis protocols, such as combinatorial chemistry. Both general and specific discussion of such techniques are set forth in Hayes, Microwave Synthesis-Chemistry at the Speed of Light, CEM Publishing (2002) (ISBN 0-9722229-0-1).
Accordingly, a new generation of instruments has been developed for this purpose, and by way of illustration and background, can be well understood by evaluating the disclosures of several co-pending and commonly assigned applications. These include published applications U.S. Pat. No. 20,020,101,310, U.S. Pat. No. 20,020,121,513, U.S. Pat. No. 20,020,117,498, U.S. Pat. No. 20,020,102,738 and WO 02/062104, and unpublished (to date) U.S. applications Ser. Nos. 09/773,898 filed Jan. 31, 2001 (“Pressure Measurement in Microwave-Assisted Chemical Synthesis”) and 10/126,838, filed Apr. 19, 2002 (“Microwave Assisted Chemical Synthesis Instrument with Controlled Pressure Release”). The contents of all of these are incorporated entirely herein by reference.
As set forth in these disclosures, more recent techniques and instruments incorporate relatively small microwave cavities that support a single or other defined modes of microwave radiation that are more suitable for promoting reactions between reactants present in very small quantities that would be difficult to heat with more conventional microwave instruments. Commercially, recently available devices include the EXPLORER™, and DISCOVER™ instruments from CEM Corporation, the assignee of the present invention. In these instruments, a single mode cavity is matched with a removable attenuator, which also serves as a support mechanism for a reaction vessel. In this manner, reaction vessels can be quickly inserted into the instrument, have microwave radiation applied to them, and then be removed for the next step in whatever analysis or synthesis of interest is taking place.
As set forth in Publication No. U.S. Pat. No. 20,020,121,513, the pressure inside of a vessel during the application of microwaves can be measured by penetrating the vessel with a needle in communication with a pressure measuring device. In the ″513 Publication, the reaction vessel is typically capped with a flexible, penetrable cover or septum through which a needle can be inserted without compromising the pressure integrity of the vessel, because of the manner in which the penetrable septum quickly surrounds and grips the penetrating needle. The annulus of the needle is in communication with a pressure-measuring device, typically a transducer, so that the pressure in the reaction can be monitored.
Although these instruments and the needle-penetrated septum arrangement for pressure measurement offer a number of advantages, there are additional types of reactions for which a physically-penetrating pressure measurement is less suitable.
For example, a pressure release may not be controllable; i.e., it may operate in an all-or-nothing fashion. Additionally, the contents of the vessel and the needle may be mutually reactive; i.e., the needle may corrode, react to form unwanted byproducts, or even catalyze an undesired or unexpected reaction. As another potential factor, certain reactions are most suitably carried out in the absence of oxygen (and thus in the absence of air) or, stated in the affirmative, in the presence of some inert gas such as nitrogen or one of the noble gases such as argon or helium. In such cases, pressure measurement using a device that penetrates into the reaction vessel and provides a communication path for fluids and gases outside of the vessel can be disadvantageous or inappropriate. Thus, in such cases it can be likewise disadvantageous to attempt to measure pressure using some sort of fluid communicating device, such as the needle, between the transducer and the vessel's contents.
Pressure measurement is, however, often an important factor in tracking the progress of certain reactions. The measured pressure can be an indication of desired products, undesired by-products, completion of a reaction, or loss of control over the reaction. Thus, resolving pressure-measurement problems by simply foregoing pressure measurement is an undesired option in many circumstances.
Accordingly, a need exists for a method of measuring pressure in such reaction vessels without penetrating the vessel during the reaction. Devices exist for such purposes, including (in a somewhat unrelated environment) U.S. Pat. No. 6,287,526, which is commonly assigned with the present application. In a more analogist environment, Personal Chemistry, Inc. (Foxboro, Mass.) provides the Emrys™ Synthesizer and Emrys™ Process Vials for this purpose.
The Emrys™ vessels nevertheless demonstrate certain of the problems with such vessels. As illustrated by Personal Chemistry (www.personalchemistry.com/products/smith_vials.xml) the vessels include a sealing metal cap that typically holds a septum in place over the mouth of the vessel. These vessels and caps will typically remain intact and maintain their seal at pressures of about twenty atmospheres or even more. They cannot, however, release intermediate pressures. Additionally, because their functional status is either pressure-sealed or fully unsealed, they typically can not or should not be opened immediately upon completion of a pressure-generating reaction. As a result, the pressure-containing vessels must either be opened in some more sophisticated fashion, or be allowed to cool sufficiently to moderate the internal pressure.
As another consideration, a number of reactions can be or should be carried out at slightly elevated pressures, or will generate slightly elevated pressures as they proceed. In such cases, the amount of pressure generated needs to be both monitored and controlled; i.e., if the increased pressure is within a desired or expected limit, the reaction should be allowed to proceed. If, however, for some reason the pressure exceeds a predetermined or desired limit, the reaction may need to be slowed or stopped, and the excess pressure may need to be released for safety purposes.
Accordingly, in addition to measuring pressure without penetrating the vessel, a corresponding need exists for sealing a vessel in a manner that permits it to accommodate a desired higher pressure, while still providing a means for handling excess pressure in a safe and reliable fashion.